Suspension device and method

ABSTRACT

A device and method for providing a suspended agent such as a contrast agent without mechanical resuspension. A volume of agent is divided into sub-volumes in a network of tubes, cells, sponges, grooves, etc. A propellant fluid flows through the network to release the suspended agent. The network may be internal to a container for the propellant fluid. Alternatively, the network may be adjacent an exit port of a container for the propellant fluid, or may be in-line between a propellant fluid container and a patient. The invention reduces sedimentation of agents into one or a few aggregates and eliminates a mechanical mixing step. The invention thus provides a uniformly suspended agent, improving patient health and safety and increasing cost and time savings.

FIELD OF THE INVENTION

[0001] The invention relates to a device and method of using the devicefor providing a suspended volume of an agent without additional mixing.

BACKGROUND

[0002] Agents that do not persist in a suspended state and sediment mustbe resuspended prior to use. One example of an agent that must beresuspended prior to use is a pharmaceutical colloid, such as a contrastagent that is injected into a patient to enhance an imaging procedure.Contrast agents are used in various types of imaging including x-ray,magnetic resonance imaging (MRI), computed tomography (CT) andultrasound (US). A contrast agent that comes out of suspension must beresuspended before placing the desired volume to be dosed into adelivery container such as a syringe. If there is a delay before thedose is injected into a patient, for example while preparing the patientor equipment, or if the infusion is extended, the agent must again besuspended before or during administration.

[0003] Resuspension of contrast agent requires mechanical manipulations,for example, removing a filled syringe positioned in an injector andremixing its contents. Additional remixing steps may delay a criticalinfusion time or, if remixing is omitted, the entire imaging proceduremay have to be repeated due to suboptimal contrast obtained. Duplicateprocedures not only put patients at increased risk and inconvenience,but are also cost- and time-inefficient. Even if the need to resuspend asingle bolus injection is not prohibitive for a given procedure,repeated bolus injections or long term continuous infusions can becomeproblematic due to agent coming out of suspension during administration.

[0004] The loss of suspension for a contrast agent at any point in adelivery system to a patient, such as in a syringe and/or in theconnecting tubing, severely limits the duration of continuous infusionsor the time between intermittent injections. The need to initiallyresuspend the colloid or other type of agent, and to further suspend ifthe agent is not used shortly after resuspension, requires eithertime-consuming effort and vigilance by the user or the use of mechanicalmixing devices. In any case, the need to resuspend an agent poses anadditional step and a possible source of error in an imaging procedure.

SUMMARY OF THE INVENTION

[0005] The invention is directed to a device that provides a suspendedagent without additional mechanical mixing. The device divides a totalvolume of a sedimenting agent into a network of sub-volumes and hasprots for an inflow and outflow of a propellant fluid to releases thesub-volumes of agent from the device. In one embodiment, the device islocated within a container in which the agent is packaged, such as avial or bottle, or in a container in which the agent is dosed, such as asyringe or bag, or in a container containing the propellant fluid. Inanother embodiment, the device is located external to a container forthe propellant fluid. In this embodiment, the device may be operablyattached to an exit port of the propellant fluid container.Alternatively, in this embodiment, the device may be positioned in-lineat any point with lines that connect the propellant fluid container witha patient connector. The device is comprised of a network of sub-volumesthat may take the form of one or more tubes, cells and/or sponges, andthat may assume any configuration such as a parallel, stairstep,helical, random and/or coiled configuration. The network may be retainedin a network holder.

[0006] The invention is also directed to a suspension device for avolume of an agent in which a container for the propellant fluid has anetwork of grooves that are integral with the container and that retaina sub-volume of the agent within the grooves. The container has a plugthat occupies an internal volume of the container and the grooves areeither integral with an internal wall of the container, or are integralwith an external wall of the plug. In either embodiment, the plugdiverts the propellant fluid flow to a variable extent from the centerof the container to the periphery of the container, thus diverting fluidflow through the grooves. The grooves may further contain substantiallyperpendicular channels at regular intervals to allow uniform filling ofthe grooves with the agent.

[0007] The invention is also directed to a method of providing a volumeof suspended agent to a patient. The method includes dividing the volumeof agent into contained sub-volumes, storing the sub-volumes in anetwork for containing sub-volumes of the agent and providing apropellant fluid under pressure to eject the sub-volumes of agentthrough the network and into a patient. The propellant fluid may behoused in a container in which the network is also located.Alternatively, the network may be external to the propellant fluidcontainer, with the network positioned either in-line between a sourceof propellant fluid and a patient, or adjacent an exit port of apropellant fluid container.

[0008] The invention is also directed to a suspension device for afolume of an imaging contrast agent. A network contains a plurality ofsub-volumes of the agent and has inflow and outflow ports for propellantfluid. The device may also have a container and network holder externalto the container.

[0009] The objectives and other advantages of this invention will befurther understood with reference to the following drawings and detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

[0010]FIG. 1 is a cross-sectional view of a syringe container with aninternal tubular network.

[0011]FIG. 1A is a view similar to FIG. 1 of an alternate embodiment ofthe invention.

[0012]FIG. 2 is a cross-sectional view of a syringe container with anexternal tubular network operably attached to a propellant fluidcontainer exit port.

[0013]FIG. 3 is an elevational view of an in-line device.

[0014]FIGS. 4A, 4B and 4C are various network embodiments andconfigurations.

[0015]FIG. 5 is a cross-sectional view of a syringe container having anintegral network.

[0016]FIG. 6 is a cross-sectional view of an integral network withchannels.

DETAILED DESCRIPTION

[0017] The device of the invention sub-divides a desired volume of anagent to suspend the agent without mechanical mixing. Resuspension iscaused by viscous fluid flow through the network of sub-volumes. As usedherein, the device is comprised of a network of structures forcontaining sub-volumes of the agent, with the entire volume of agentcontained in the network component sub-volumes. As will be described,the device may be located in the same container that contains propellantfluid to eject the agent from the network (container packageembodiment). Alternatively, the device may be located adjacent an exitport of a propellant fluid container (add-on embodiment), or may bepositioned in-line at any point in a fluid path between the propellantfluid container and the ultimate deposit site such as a patient (in-lineembodiment). As used herein, a propellant fluid is one that is used toeject the agent from the network of tubes, cells, etc. As used herein, anetwork is defined as a collection of structures which contain theentire desired volume of agent in sub-volumes, and hence increase thesurface area of the agent over which the propellant fluid must flow, inthe device. In one embodiment, the network has a common exit port, andagent sub-volumes are ejected from the network at a substantially equalrate. The network may encompass tubes, cells, sponges, etc. and is notlimited by volume or configuration.

[0018] The device sub-divides a volume of an agent to prevent it fromsettling or sedimenting into one or a few dense aggregates without theneed for mechanical mixing or suspending prior to use, and thus reducesor eliminates the problem of remixing or resuspending an agent that hascome out of suspension prior to use. Use may be either preparing aninjection dose by transferring the desired volume of agent from apackage to a dosing container such as syringe, or injecting the dosingvolume of agent into a patient. This problem may occur with contrastagents, either while in their package or portioned in a container suchas a syringe for injecting into a patient about to undergo an imagingprocedure. The invention solves the problem by subdividing the volume ofthe agent to prevent separation or aggregation of the agent from thesuspending liquid.

[0019] Dividing a uniformly suspended contrast agent or other agent intoa network of sub-volumes rather than a single large volume inhibits theparticles from either floating or precipitating into one or more largermasses or aggregates. The invention thus reduces or obviates the needfor mixing before or during a process, such as an infusion process. Thisincreases the quality, safety, and cost- and time- efficiencies of theprocess.

[0020] With reference to FIG. 1, a network 8 a containing dividedsub-volumes of an agent 12 is internal to a container 10 for propellantfluid 16. The container 10 may be a syringe 14 or other types ofcontainers which include but are not limited to vials, bags havingflexible or semi-flexible walls, bottles of either glass or plastic,etc. The agent 12 contained in the network 8 a is ejected from thecontainer 10 as propellant fluid 16 flows through the network 8 a anddisplaces the agent 12. The propellant fluid 16 is any viscous fluid(liquid or gas) that is biocompatible. The propellant fluid may be adiluent for the agent 12 such as normal saline, water, buffer, etc. Thepropellant fluid 16 may also be a contrast agent that is different fromthe agent 12 injected for the imminent imaging procedure.

[0021] The network 8 a may be any structure that serves to contain asub-volume of the desired total volume of an agent 12 in a unit area.The network 8 a may be contained in a network holder 22. The network 8 amay be tubes 18 which, as used herein, encompass tubules, microtubules,channels, or other types of hollow cylinders that convey a fluid or thatfunction as a passageway, whereby a volume of agent 12 is divided intosub-volumes of any size. There are numerous configurations of the tubes18 that can be used to sub-divide the volume of agent 12. These include,but are not limited to, a single long tube 18 as best shown in FIG. 1 ora collection of tubes 18 a as shown in FIG. 1A. The tubes 18 may be inany configuration, such as one or more coils or helices, an angular orstairstep configuration, and/or even random configurations. A collectionof tubes 18 may similarly be one or more coils or helices, an angular orstairstep configuration, and/or even random configurations, or may bearranged in a parallel configuration (FIG. 1A). The geometries andconfigurations of the network 8 may be combined in either regular orrandom configurations. While FIGS. 1 and 1A show tubes 18 positioned ina syringe 14 without any accompanying support, other configurations arecontemplated. For example, the tubes 18 may be positioned within anetwork holder 22 (FIGS. 2 and 3), or may be supported or held in asyringe 14 or network holder 22 by a fixture such as 24 (shown inphantom lines in FIG. 1) which may extend for part of or all of thelength of the network 8.

[0022] With reference to FIG. 2, a dose delivery container 10 that is asyringe 14 is shown with a network holder 22 containing the network 8external to the syringe 14. The network 8 c is packaged within a networkholder 22, which may be any container in which the network is housed orretained and may be made of any biocompatable material. The networkholder 22 containing the network 8 c may be separable from the syringe14 or other container 10 and attached to an exit port 24 of the syringe14 or container 10. The network holder 22 for the network 8 c may alsobe manufactured as part of the container 10, which may be useful as apre-packaged embodiment of the invention. In a non-pre-packagedembodiment, the network holder 22 may be attached to an exit port 24using, for example, connectors 26 such as luer fittings. The exit port24 of the syringe 14 may be fitted with luer fittings, such as Luer-Lok®caps (Becton-Dickinson), or may have luer fittings such as metal, brassor glass luer tips attached. As previously described, a support orfixture 30 for the tubes 28 may be used, and the support 30 and tubes 28may be contained in a network holder 22. As one alternative, the support30 and tubes 28 may be contained directly in the container 10. Asanother alternative, the tubes 28 in a network holder 22 may beunsupported as shown in FIG. 2.

[0023] While FIG. 2 illustrates a network holder 22 which is attached toa syringe 14, other embodiments are contemplated. With reference to FIG.3, the network (not shown) contained in a network holder 22 is shown inan in-line embodiment. The network holder 22 is fashioned withconnectors 26 at both an inflow port 32 and an outflow port 34. Tubingis connected to connectors 26 to carry propellant fluid 16 from asyringe to holder 22 and from holder 22 to a patient. The connectors 26may be the same or different at the inflow 32 and outflow 34 ports andmay be any type such as luer fittings, as previously described. Networkholder 22 and the network inside may be configured symmetrically, sothat the orientation of the network holder 22 in an in-flow embodimentneed not be a concern; i.e., there is no back-to-front or front-to-backlimitation. Agent 12 can be removed from the network within the networkholder 22 upon pressure from a propellant fluid 16.

[0024] A network 8 that is internal to a container 10 such as a syringe14 need not be housed in a network holder 22. As seen in FIGS. 1 and 1A,the network 8 a, 8 b of tubes 18 or other structures may be positioneddirectly within the barrel 36 of the syringe 14. In an alternativeembodiment, the network 8 that is internal to a syringe 14 or othercontainer 10 may also be housed in a network holder 22. In eitherembodiment, the barrel 36 of the syringe 14 may contain a propellantfluid 16 that, upon initiation of flow, provides pressure to release oreject the agent 12 from the network 8. The propellant fluid 16 need notbe pre-filled in the barrel 36 of the syringe 14, but instead may beadded to the barrel 36 of the syringe 14.

[0025] The sub-dividing volume structure of tubes 18 in the network 8may assume a variety of geometries and configurations. As shown in FIGS.1A, 2, 4A, 4B and 4C, the tubes 18 may be straight, coiled, helical, inrandom filaments 38, in an angular or stairstep (not shown)configuration, or may have other configurations. All of thesealternatives are appropriate for use in any of the illustratedembodiments. The sub-dividing network 8 need not encompass tubes 18 atall; all shown in FIGS. 4A, 4B and 4C, the network 8 d, 8 e and 8 frespectively, may be a series of discrete cells 42 (see FIG. 4B), or mayhave a sponge 44 type of structure (see FIG. 4A). In a cell 42structure, the agent 12 is retained in or on discreet cells 42. In asponge 44 structure, the agent 12 is either absorbed in or adsorbed onthe sponge 44, rather than contained within tubes 18 or cells 42. A cell42 or sponge 44 structure may also be used effectively in a networkholder 22 separate from a syringe 14. In any embodiment, the network 8may be configured so that there is a non-uniform direction for allsub-volumes, that is, there is no single upward, downward or lateraldirection for all sub-volumes.

[0026] With reference to FIG. 5, a network 8 g that is integral with thecontainer 10 is shown. In this embodiment, the network 8 g is fabricatedas grooves or channels 48 that are etched or otherwise manufacturedwithin the container 10 itself. For example, a syringe 14 may have acylindrical plug 46 disposed in the barrel 36, where the plug 46 hasparallel or spiral grooves 48 in its outer surface. The grooves 48contain the agent 12 between the syringe 14 inner wall 50 and barrel 36.As shown in FIG. 6, the grooves 48 may contain substantiallyperpendicular channels 60 at one or more regularly spaced intervals. Thechannels 60 permit rapid and uniform filling of the network 8 with agent12 added into one side of a container 10 when the other side of thecontainer 10 is sealed. In another embodiment, the syringe 14 has acylindrical plug 46 disposed in the barrel 36 as previously described,where the inner wall 50 of the syringe 14 has parallel or spiral groovesin its structure. The grooved structures 48 may also be used in aseparate network holder 22. In these embodiments, the grooved structure48 comprises the network 8 which sub-divides the volume of agent 12. Itwill thus be appreciated that the network 8 may assume a variety offorms and configurations whereby a volume of agent 12 can be sub-dividedinto smaller volumes with increased surface area of the agent 12 overwhich the propellant fluid 16 flows to reduce sedimentation.

[0027] The network 8, whether in the form of tubes 18, cells 42 orsponges 44, may be made of any biocompatable material that can withstandsterilization and is inert with respect to the agent 12, the propellantfluid 16, and the container 10. Examples of such materials for a tubular18 network include biocompatable tubing such as polyethylene,polypropylene, silicon, rubber, etc., for example, Tygon® tubing(halogenated vinyl plastic, Norton Plastics). Tubes 18 used in kidneydialysis devices, such as cellulose tubes 18 having a nominal diameterof 200 μm, may also be used in the invention In a network 8 e havingcells or voids, the cells 42 may be produced by incomplete fusion ofpieces of fusable material such as thermoplastics or metals. The cells42 may be made of Delrin™, polycarbonate such as Lexan™, polyethylene,polypropylene, silicon, rubber, etc. In a network 8 d having a sponge 44structure, the sponge 44 may be made of porous Delrin™, porpouspolycarbonate such as Lexan™, porous polyethylene, porous polypropylene,porous silicon, porous rubber, etc.

[0028] The size and volume of the network 8, container 10, and networkholder 22 may vary, depending upon a number of factors. These factorsinclude the volume of agent 12, the size of the container 10, theduration of the imaging or other procedure to be performed, etc. Thereis neither a maximum nor a minimum volume for the network 8, container10, or network holder 22, and an exponential range of volumes iscontemplated by the invention. For embodiments in which the network 8 isinternal or integral with the container 10, however, the volume of agent12 contained within the network 8 is at most one-half the volume ofpropellant fluid 16 in the container 10 This ensures that substantiallyall the agent 12 will be released from the network 8 by the flow ofpropellant fluid 16. For example, volumes of contrast agent 12 injectedfor enhanced ultrasound imaging may range from 1 ml to about 10 ml. Asan example, a 3 ml volume of agent would require using about a 10 mlsyringe 14, with the tubular 18 or other structure of the network 8containing 3 ml agent 12 and the remaining volume of the syringe 14containing at least 3 ml, and more typically 4-5 ml, of propellant fluid16. A 3 ml volume of agent 12 may be sub-divided in a syringe 14 havingten threads or grooves 48 per inch, with the threads or grooves 48 onemillimeter deep, each thread or groove 48 containing about 0.3 ml agent12.

[0029] The container 10 and/or network holder 22 may be manufacturedhaving the network 8 preloaded with a uniformly mixed suspension ofagent 12 such as a pharmaceutical colloid. The container 10 and/ornetwork holder 22 may have both an entry port 54 and an exit port 56with appropriate fittings 26 such as luer locks for connection tostandard tubing or catheters, as is known to one skilled in the art(FIG. 3). To eject the agent 12 in the network 8 from the exit port 56of the container 10 or network holder 22 and into the patient through apatient connector line, propellant fluid 16 may be injected into theentry port 54 or, alternatively, pressure may be applied to thepropellant fluid 16 already in the container 10. The container 10 mayalso have a single exit port 56 and a plunger 58, with liquid 60 in theopposite end, to permit use as a prefilled syringe (FIG. 1).

[0030] The specific location, position and configuration of the network8 may depend upon an intended use. For example, an agent containing agas other than air should be housed in a container 10 that has beenpurged of air. A container 10 made of glass may be rendered air-tightmore easily than a plastic syringe, and thus is preferable for thisagent. Likewise, a network 8 that is internal rather than external ispreferred for use with an agent that contains a gas other than air. Thisallows the propellant fluid 16 to be purged of air and become saturatedwith the agent-containing gas, maintaining a substantially anaerobicenvironment prior to injection.

[0031] One advantage of the invention is that it eliminates the need forresuspension of agents 12 that may come out of suspension, either intheir original container 10 or in a dose delivery container such as asyringe 14. Conventional containers 10 require mechanical devices ormanipulations to maintain colloids such as a contrast agent 12 insuspension. By eliminating the need for prior resuspension of the agent12 for single-bolus injection, the device and method of the presentinvention provides a competitive advantage for injectable agents 12. Inaccordance with the principles of the present invention, a syringe 14having a network 8 containing agent 12 can remain resuspendable for morethan five months.

[0032] Maintaining the agent 12 in a substantially fully resuspendablestate assures consistent quality and reduced sensitivity to usertechnique. The agent 12 may be shipped already prepackaged in thenetwork 8. This arrangement has the potential to reduce susceptibilityof agents, such as microbubble preparations, to mechanical vibration andshock which may decrease the integrity of the agent 12. Dividing thevolume of agent 12 into sub-volumes also allows it to be more quicklypreheated to a desired temperature, facilitating the efficiency of theentire imaging procedure.

[0033] Another advantage of the invention is that the colloid or otheragent 12 may be released, ejected or expelled from the exit port 56 ofthe container 10 by injecting a propellant fluid 16. This precludes theneed to draw the pharmaceutical or contrast agent 12 into a syringe 14for injection, and provides similar advantages as enjoyed by pre-filledsyringes.

[0034] Still another advantage of the invention is that, in thoseembodiments such as FIGS. 2 and 3 where network 8 is external to thesyringe 14, the exit port 56 of the dose delivery container 10 ornetwork holder 22 may be connected to a short angiocatheter (not shown)that is very close to a venous or arterial puncture site in a patient.This arrangement prevents loss of suspension of agent 12 that wouldoccur inside a longer catheter, and permits use of a manual or powersyringe located a substantial distance away from the patient, whilepreventing the need for the agent 12 to maintain resuspendable in themanual or power syringe 14 and connecting tubing. Instead, the manual orpower syringe and tubing need only contain a non-colloidal fluid thatdoes not require mixing or resuspending during long injection times.

[0035] A further advantage of the invention is realized with an optionalbuilt-in plunger 58 in the syringe 14. A built-in plunger 58 permits useof the device as a manual syringe 14 or with a small, battery-operatedpower injector at the end of a very short angiocatheter. In either case,the filled syringe 14 could be located very close to a venous orarterial puncture site, precluding the need to maintain the agent 12resuspended in a long catheter for infusion into a patient. Thisembodiment also precludes the need for a fluid-filled syringe 14connected to the entry port 54 of the dose delivery container 10 inorder to eject the agent 12 from the exit port 56 of the dose deliverycontainer 10.

[0036] It should be understood that the embodiments of the presentinvention shown and described in the specification are exemplaryembodiments contemplated by the inventor and are not limiting in anyway. For example, the invention is not limited to use in the clinicalarea and may be used in research applications, as well as in otherindustries where uniformly suspended agents are needed, such as the foodand beverage industries. In such cases, for example, the propellantfluids 16 may also include oils, epoxy resins, sugars, etc., dependingupon the application. Therefore, various changes, modifications oralterations to these embodiments may be made or resorted to withoutdeparting from the spirit of the invention and the scope of thefollowing claims.

What is claimed is:
 1. A suspension device for a volume of an agentcomprising a network to contain a plurality of sub-volumes of said agentand ports for an inflow and an outflow of a propellant fluid to releasesaid agent from said network.
 2. The device of claim 1 wherein thenetwork is selected from the group consisting of a tube, a cell, asponge and combinations thereof.
 3. The device of claim 1 wherein thenetwork is internal to a container.
 4. The device of claim 3 wherein thecontainer contains said propellant fluid.
 5. The device of claim 3wherein said container is selected from the group consisting of asyringe, a bag, a bottle and a vial.
 6. The device of claim 1 furthercomprising a network holder and a container holding said propellantfluid, wherein the network is external to said container and is retainedin said network holder.
 7. The device of claim 6 wherein said network isoperably connected adjacent an exit port of said container.
 8. Thedevice of claim 6 wherein said network is connected in-line between saidpropellant fluid container and a patient.
 9. The device of claim 2wherein the tubes have a configuration selected from the groupconsisting of random, parallel, coiled, helical and combinationsthereof.
 10. The device of claim 1 wherein said network contains saidagent.
 11. A method of providing a volume of a suspended agent to apatient comprising (a) dividing said volume into a plurality ofsub-volumes, (b) storing said sub-volumes in a network for containingsub-volumes of said agent, and (c) releasing said sub-volumes of saidagent into said patient through a patient connector by providing apropellant fluid under pressure through said network to release saidsuspended agent.
 12. The method of claim 11 further comprisingcontaining said propellant fluid in a container, wherein the network isinternal to said container for said propellant fluid.
 13. The method ofclaim 12 wherein said container is a dose delivery container.
 14. Themethod of claim 12 wherein said container is a packaging container. 15.The method of claim 13 wherein said dose delivery container is selectedfrom the group consisting of a manual syringe, a power syringe and abag.
 16. The method of claim 11 further comprising containing saidpropellant fluid in a container, wherein the network is external to saidcontainer for said propellant fluid.
 17. The method of claim 16 whereinsaid container has an exit port and said network is operably connectedadjacent said exit port.
 18. The method of claim 16 wherein said networkis operably connected in-line between said container and said patientconnector.
 19. The method of claim 11 wherein said network is selectedfrom the group consisting of a tube, a channel, a sponge andcombinations thereof.
 20. The method of claim 11 wherein said agent isreleased by injecting said propellant fluid into an entry port of saidcontainer.
 21. A suspension device for a volume of an agent comprising(a) a container for a propellant fluid, said container having an entryport and an exit port for said fluid, (b) a network of grooves integralwith said container for retaining a plurality of sub-volumes of saidagent in said grooves, and (c) a plug occupying an internal volume ofsaid container for diverting a flow of said fluid through said grooves.22. The device of claim 21 wherein said grooves are integral in aninternal wall of said container.
 23. The device of claim 21 wherein saidgrooves are integral in an external wall of said plug.
 24. The device ofclaim 21 wherein said plug occupies substantially an entire internalvolume of said container.
 25. The device of claim 21 wherein saidgrooves further contain substantially perpendicular channels at aregular interval to uniformly fill said grooves with said agent.
 26. Asuspension device for a volume of an imaging contrast agent comprising anetwork to contain a plurality of sub-volumes of said agent and portsfor an inflow and an outflow of a propellant fluid to release said agentfrom said network.
 27. The device of claim 26 further comprising anetwork holder and a container holding said propellent fluid, whereinthe network is external to said container and is retained in saidnetwork holder.
 28. The device of claim 26 wherein said network containssaid agent.